Epilepsy is a complex genetic disease with a prevalence of about 1% worldwide. So far, only a few epilepsy genes have been identified in unusually large, high-density pedigrees. However, their contribution in the general epilepsy population appears to be limited and many mutations seem to raise seizure susceptibility unspecifically, since divergent seizure types are associated with them. Our aims for this grant are to look for further genes for epilepsy but also specifically for genetic elements that determine the absence seizures in a clinically distinct subform of epilepsy, i.e. Childhood Absence Epilepsy (CAE). Using a novel statistical approach, we have already identified areas containing genes with high biological relevance to epilepsy in a genome wide association study (GWAS). In a pathway analysis we found that a majority of identified genes map to a network involving Cell-To-Cell Signaling and Interaction, Nervous System Development and Function, and Cell Death. Furthermore, we have identified association peaks in highly conserved intergenic chromosomal regions, raising the possibility of the involvement of regulatory elements in CAE. We will confirm our findings in an independent sample of CAE patients and in addition, we will also investigate the involvement of chromosomal structural variants in CAE. We will then determine the sequence variants underlying these association results by Next-Gen sequencing. We will be in an excellent position to discover novel pathways that lead to epileptogenesis that go beyond the already established mechanisms of membrane excitability and synaptic transmission. PUBLIC HEALTH RELEVANCE: Epilepsy is a common, genetically complex disease with a prevalence of about 1% worldwide. So far, only a few epilepsy genes have been identified in unusually large, high-density pedigrees. However, their contribution in a general epilepsy population is minimal and mutations seem to raise seizure susceptibility unspecifically. Our aims for this grant are to look for further genes for epilepsy but also specifically for genes that determine the absence seizures in a clinically distinct subform of epilepsy, i.e. Childhood Absence Epilepsy (CAE).